The health consequences of smoking are primarily perceived to be cancer, cardiovascular disease, and chronic pulmonary disease, but acute pulmonary consequences of exposure to cigarette smoke are likely to be as or more important with respect to overall morbidity and mortality from smoking. However, there has been little research on smoking and acute lung injury (ALI), a common cause of acute respiratory failure in critically ill patients. Cigarette smoking and secondhand smoke exposure are associated with a nearly three- fold increase in the odds of developing ALI after severe blunt trauma, but the effects of cigarette smoke exposure on susceptibility to infection-associated ALI, the most common type of ALI, are unknown. This project will increase our understanding ofthe adverse health consequences of tobacco use by quantifying the increased susceptibility to infection-related ALI. Understanding the impact of smoking and secondhand smoke exposure on infection-related ALI will have major implications forthe regulation of tobacco products because ofthe large immediate cost burden of ALI and the potentially rapid impact of changes in cigarette smoke exposure on the incidence of ALI and its associated mortality burden and costs. We hypothesize that cigarette smoke exposure before infection primes patients to develop acute respiratory failure from ALI. We will leverage the infrastructure of our ongoing prospective cohort of critically ill patients with severe infection and our experience with animal models of ALI and cigarette smoke exposure to 1) quantify the strength, dose-response curve, and time course of the association between cigarette smoke exposure, as measured by validated biomarkers, and the development of ALI in patients admitted to the hospital with severe infection; 2) test the effects of cigarette smoke exposure and varying nicotine content on the development of infection-related ALI in mouse models, with a focus on identifying plasma biomarkers of tobacco-related lung epithelial or endothelial injury that can then be tested in critically ill patients; and 3) validate the asso(:;iation between biomarkers of tobacco-related lung epithelial and endothelial injury and the development of ALI in critically ill human subjects with severe infection. The results ofthis project will inform more accurate models ofthe economic and public health effects of cigarette smoke exposure. This~project will also identify biomarkers of tobacco-related lung injury that can be used in future studies of toxicity and take the critical first steps towards determining which constituents of tobacco smoke promote lung injury, including studies of the roles of nicotine and acrolein in tobacco smoke toxicity, with important regulatory implications. RELEVANCE (See instructions'!: By advancing our understanding of the association between cigarette smoke exposure and the common and costly syndrome of ALI, this research will have major implications for FDA models ofthe impact of changes in cigarette smoke exposure on health care costs and public health outcomes. This research will also quantify the magnitude of change of biomarkers of exposure that can be translated into meaningful changes in ALI risk and identify functional biomarkers that reflect the short-term pulmonary toxicity of tobacco products, for use in future studies. Finally, this research will take the essential first steps towards identifying the constituents of cigarette smoke with the greatest impact on lung injury.